Abstract African-Americans are a particularly vulnerable group of smokers who experience high levels of addiction and smoking-related disease risk compared to whites, yet there has been little systematic research in this area. Our proposal seeks to clarify the nature of racial differences in smoking behavior and exposure to tobacco smoke toxins (African-Americans vs whites), and their relationship to differences in the pharmacology of nicotine (metabolism and reinforcement). An ultimate objective is to use this knowledge to aid in the development of more effective smoking cessation interventions for African-Americans. Four studies are proposed: #1: We will first use stable isotope methodology to characterize nicotine metabolic pathways, and will then determine the association (in African-Americans) of metabolism/PK phenotypes with genetic polymorphisms in the genes responsible for nicotine metabolism. #2: We will compare changes in smoking behavior, extent of nicotine titration, and tobacco smoke toxin exposure that result from switching from regular yield to light cigarettes in African-Americans vs. whites. We hypothesize that African-Americans smoke in a manner to get positive reinforcement (nicotine peak-seekers) more than do whites, who are hypothesized to smoke in a manner to maintain nicotine levels throughout the day (nicotine trough-maintainers), and that this will influence the response to switching. #3, 4: We will examine the effects of acute administration (single dose) vs. longer term (7 day) treatment with smoking cessation medications on smoking behavior, reinforcement and tobacco smoke toxin exposure. We propose that African-American and white smokers will respond differently to two medications with different mechanisms of action (transdermal nicotine and varenicline). Secondary analyses using data pooled across studies will examine the relationship of smoking behaviors and tobacco smoke toxin intake to each of these elements: (a) nicotine clearance, (b) use of menthol vs. non-menthol cigarettes and (c) motivations for smoking and dependence measures. Chemistry activities will include (1) synthesis of stable isotope-labeled compounds, including nicotine, cotinine and 3-hydroxy-cotinine for quantitative metabolic studies; and (2) developing and applying GC- MS and LC-MS/MS methods to quantify nicotine and metabolites and tobacco smoke carcinogens for metabolism and exposure assessment studies. Narrative African-Americans are a particularly vulnerable group of smokers who experience high levels of addiction and smoking-related disease risk compared to whites, yet there has been little systematic research in this area. Our proposal seeks to clarify the nature of racial differences in smoking behavior and exposure to tobacco smoke toxins (African-Americans vs whites), and their relationship to differences in the pharmacology of nicotine (metabolism and reinforcement). An ultimate objective is to use this knowledge to aid in the development of more effective smoking cessation interventions for African-Americans.